2. • The most common red cell disorders are those
that lead to anemia, a state of red cell
deficiency.
• White cell disorders, by contrast, are most
often associated with excessive proliferation
resulting from malignant transformation.
• Derangements in blood coagulation may
result in hemorrhagic diatheses (bleeding
disorders).
3. Red Cell Disorders
• Disorders of red cells can result in anemia or, less
commonly, polycythemia (an increase in red cells
also known as erythrocytosis).
• Anemia is defined as a reduction in the oxygen-
transporting capacity of blood, resulting from a
decrease in the red cell mass to subnormal levels.
• Anemia can stem from bleeding, increased red
cell destruction, or decreased red cell
production.
5. • Anemia also can be classified on the basis of red
cell morphology, which often points to particular
causes. Features that provide etiologic clues
include the size, color, and shape of the red cells.
• Mean cell volume (MCV): the average volume per
red cell, expressed in femtoliters (cubic microns)
• Mean cell hemoglobin (MCH): the average mass
of hemoglobin per red cell, expressed in
picograms
• Mean cell hemoglobin concentration (MCHC): the
average concentration of hemoglobin in a given
volume of packed red cells, expressed in grams
per deciliter
• Red cell distribution width (RDW): the coefficient
of variation of red cell volume
7. ANEMIA OF BLOOD LOSS:
HEMORRHAGE
• Anemia of blood loss can be divided into anemia
caused by acute bleeding (hemorrhage) and
anemia caused by chronic blood loss (described
later).
• The effects of acute bleeding are mainly due to
the loss of intravascular volume, which if
massive can lead to cardiovascular collapse,
shock, and death.
• If blood loss exceeds 20% of blood volume, the
immediate threat is hypovolemic shock rather
than anemia.
8. • If the patient survives, hemodilution begins at
once and achieves its full effect within 2 to 3
days; only then is the full extent of the red cell
loss revealed.
• The anemia is normocytic and normochromic.
• Recovery from blood loss anemia is enhanced by
a compensatory rise in the erythropoietin level,
which stimulates increased red cell production
and reticulocytosis within a period of 5 to 7 days.
• With chronic blood loss, iron stores are gradually
depleted. Iron is essential for hemoglobin
synthesis and erythropoiesis, and its deficiency
leads to a chronic anemia of underproduction.
9. HEMOLYTIC ANEMIA
• Hemolytic anemias are a diverse group of disorders
that have as a common feature accelerated red cell
destruction (hemolysis). By definition, the red cell life
span is shortened to less than its normal 120 days,
often markedly so.
• Regardless of cause, low tissue O2 levels trigger
increased erythropoietin release from the kidney,
which in turn stimulates the growth of erythroid
elements and increased release of reticulocytes from
the bone marrow.
• Thus, erythroid hyperplasia and reticulocytosis are
hallmarks of all hemolytic anemias.
10. • Extravascular hemolysis is caused by defects
that increase the destruction of red cells by
phagocytes, particularly in the spleen.
• Findings that are relatively specific for
extravascular hemolysis include the following:
• Hyperbilirubinemia and jaundice, stemming from
degradation of hemoglobin in macrophages
• Varying degrees of splenomegaly due to “work
hyperplasia” of phagocytes in the spleen
• If long-standing, formation of bilirubin-rich
gallstones (pigment stones) and an increased risk
of cholelithiasis
11. • Intravascular hemolysis, by contrast, is characterized
by injuries so severe that red cells literally burst
within the circulation.
• Findings that distinguish intravascular hemolysis from
extravascular hemolysis include the presence of the
following:
• Hemoglobinemia, hemoglobinuria, and
hemosiderinuria. Hemoglobin released into the
circulation is small enough to pass into the urinary
space. Here, it is partially resorbed by renal tubular
cells and processed into hemosiderin, which is then
lost in the urine when renal tubular cells are sloughed.
• Loss of iron, which may lead to iron deficiency if
hemolysis is persistent. By contrast, iron recycling by
phagocytes is very efficient, and so iron deficiency is
not a feature of extravascular hemolytic anemias.
12. Hereditary Spherocytosis
• This disorder stems from inherited (intrinsic)
defects in the red cell membrane that lead to
the formation of spherocytes, nondeformable
cells that are highly vulnerable to
sequestration and destruction in the spleen.
13. • Clinical Features.
• The characteristic features are anemia,
splenomegaly, and jaundice.
14. Sickle Cell Anemia
• Hemoglobinopathies are a group of hereditary
disorders caused by inherited mutations that lead
to structural abnormalities in hemoglobin. Sickle
cell anemia, the prototypic hemoglobinopathy, is
caused by a mutation in β-globin that creates
sickle hemoglobin (HbS).
• Clinical Features. From its onset, the disease runs
an unremitting course punctuated by sudden
crises. Homozygous sickle cell disease usually is
asymptomatic until 6 months of age when the
shift from HbF to HbS is complete.
16. Clinical features
• Among the most common and serious of
these vasoocclusive crises are the following:
• Hand-foot syndrome, resulting from infarction
of bones in the hands and feet, is the most
common presenting symptom in young
children.
17. • Acute chest syndrome, in which sluggish blood
flow in inflamed lung (e.g., an area of
pneumonia) leads to sickling within hypoxemic
pulmonary beds. This exacerbates pulmonary
dysfunction, creating a vicious circle of
worsening pulmonary and systemic
hypoxemia, sickling, and vasoocclusion. Acute
chest syndrome may also be triggered by fat
emboli emanating from infarcted bone.
18. • Stroke, which sometimes occurs in the setting
of the acute chest syndrome. Stroke and the
acute chest syndrome are the two leading
causes of ischemia-related death.
• Proliferative retinopathy, a consequence of
vasoocclusions in the eye that can lead to loss
of visual acuity and blindness.
19. Thalassemia
• Thalassemias are inherited disorders caused
by mutations in globin genes that decrease
the synthesis of α- or β-globin.
• Decreased synthesis of one globin results not
only in a deficiency of Hb, but also in red cell
damage that is caused by precipitates formed
from excess unpaired “normal” globin chains.
• α-Thalassemia
• β-Thalassemia
20. β0, in which no β-globin chains are produced; and β+, in which there is reduced
(but detectable) β-globin synthesis.
21.
22. Glucose-6-Phosphate Dehydrogenase
Deficiency
• Red cells are constantly exposed to both
endogenous and exogenous oxidants, which
are normally inactivated by reduced
glutathione (GSH). Abnormalities affecting
enzymes responsible for the synthesis of GSH
leave red cells vulnerable to oxidative injury
and hemolysis.
23. Pathogenesis
• G6PD deficiency is associated with transient
episodes of intravascular hemolysis caused by
exposure to an environmental factor (usually
infectious agents or drugs) that produces
oxidant stress.
• Incriminated drugs include antimalarials (e.g.,
primaquine), sulfonamides, nitrofurantoin,
phenacetin, aspirin (in large doses), and
vitamin K derivatives.
24. • These oxidants, such as hydrogen peroxide, are
normally sopped up by GSH, which is converted
to oxidized GSH in the process.
• Because regeneration of GSH is impaired in
G6PD-deficient cells, oxidants are free to “attack”
other red cell components including globin
chains. Oxidized hemoglobin denatures and
precipitates, forming intracellular inclusions
called Heinz bodies, which can damage the red
cell membrane so severely that intravascular
hemolysis results.
25. Paroxysmal Nocturnal
Hemoglobinuria
• Paroxysmal nocturnal hemoglobinuria (PNH) is a
hemolytic anemia that stems from acquired
mutations in PIGA, a gene required for the
synthesis of phosphatidylinositol glycan (PIG),
which serves as a membrane anchor for many
proteins.
• The pathogenic mutations in PNH occur in an
early hematopoietic progenitor that is capable of
giving rise to red cells, leukocytes, and platelets.
26. • The nocturnal hemolysis that gives PNH its
name occurs because complement fixation is
enhanced by the decrease in blood pH that
accompanies sleep (owing to CO2 retention).
• The most feared complication of PNH is
thrombosis, which often occurs within
abdominal vessels such as the portal vein and
the hepatic vein.
27. Immunohemolytic Anemia
• Immunohemolytic anemia is caused by
antibodies that bind to determinants on red cell
membranes.
• These antibodies may arise spontaneously or be
induced by exogenous agents such as drugs or
chemicals. Immunohemolytic anemia is
uncommon and is classified based on (1) the
nature of the antibody and (2) the presence of
predisposing conditions
• Coombs test?????
29. Warm Antibody Immunohemolytic
Anemia
• In this entity, hemolysis results from the binding
of high-affinity autoantibodies to red cells, which
are then removed from the circulation by
phagocytes in the spleen and elsewhere.
• In addition to frank erythrophagocytosis,
incomplete consumption (“nibbling”) of
antibodycoated red cells by macrophages
removes membrane and transforms red cells into
spherocytes, which are rapidly destroyed in the
spleen, just as in hereditary spherocytosis.
30. Cold Antibody Immunohemolytic
Anemia
• Cold antibody immunohemolytic anemia usually
is caused by low-affinity IgM antibodies that bind
to red cell membranes only at temperatures
below 30°C, such as occur in distal parts of the
body (e.g., ears, hands, and toes) in cold weather.
• Sludging of blood in capillaries because of
agglutination often produces Raynaud
phenomenon in the extremities of affected
individuals.
31. Hemolytic Anemia Resulting From Mechanical
Trauma to Red Cells
• Hemolysis of red cells due to their exposure to
abnormal mechanical forces occurs in two major
settings. Clinically significant traumatic hemolysis
is sometimes produced by defective cardiac valve
prostheses, which may create sufficiently
turbulent blood flow to shear red cells (the
blender effect). More commonly, it occurs
incidentally during an activity involving repeated
physical pounding of one or more body parts
(e.g., marathon racing, karate chopping, bongo
drumming).
32. • Microangiopathic hemolytic anemia is observed
in pathologic states in which small vessels
become partially obstructed or narrowed by
lesions that predispose passing red cells to
mechanical damage
• The most frequent of these conditions is
disseminated intravascular coagulation (DIC), in
which vessels are narrowed by the intravascular
deposition of fibrin. mechanical damage.
33. Malaria
• It is estimated that malaria affects 500 million
and kills more than 1 million people per year,
making it one of the most serious afflictions of
humans.
• Malaria is endemic in Asia and Africa, but with
widespread jet travel cases are now seen all over
the world. It is caused by one of five types of
protozoa. Of these, the most important is
Plasmodium falciparum, which causes tertian
malaria.
35. Clinical Features
• Episodic shaking, chills, and fever coincide with
this release. Hemolytic anemia of varying severity
is a constant feature.
• Cerebral malaria associated with P. falciparum is
rapidly progressive; convulsions, coma, and death
usually occur within days to weeks.
• With appropriate chemotherapy, the prognosis
for patients with most forms of malaria is good;
however, falciparum malaria is becoming more
difficult to treat due to the emergence of drug-
resistant strains
36. ANEMIA OF DIMINISHED
ERYTHROPOIESIS
• Anemias of diminished erythropoiesis include
those caused by an inadequate dietary supply of
nutrients, particularly iron, folic acid, and vitamin
B12.
• Other anemias of this type are associated with
bone marrow failure (aplastic anemia), systemic
inflammation (anemia of chronic inflammation),
or bone marrow infiltration by tumor or
inflammatory cells (myelophthisic anemia).
37. Iron Deficiency Anemia
• Deficiency of iron is the most common
nutritional deficiency in the world and results
in clinical signs and symptoms that are mostly
related to anemia.
• The factors responsible for iron deficiency
differ in various populations and are best
understood in the context of normal iron
metabolism.
38. • The normal total body iron mass is about 2.5 g
for women and 3.5 g for men.
• Approximately 80% of functional body iron is
present in hemoglobin, with the remainder
located in myoglobin and iron-containing
enzymes (e.g., catalase, cytochromes).
• Serum ferritin, Assessment of bone marrow
iron
39.
40. Pathogenesis
Iron deficiency arises in a variety of settings:
• Chronic blood loss is the most important cause of
iron deficiency anemia in the Western world.
• In the developing world, low intake and poor
bioavailability because of predominantly
vegetarian diets are the most common causes of
iron deficiency.
• Increased demands not met by normal dietary
intake occur worldwide during pregnancy and
infancy.
• Malabsorption can occur with celiac disease or
after gastrectomy.
41. Clinical Features.
• In most instances iron deficiency anemia is mild
and asymptomatic. Nonspecific manifestations,
such as weakness, listlessness, and pallor, may be
present in severe cases. With long-standing
anemia, abnormalities of the fingernails,
including thinning, flattening, and “spooning,”
may appear.
• A curious but characteristic neurobehavioral
complication is pica, the compunction to consume
nonfoodstuffs such as dirt or clay.
42. Anemia of Chronic Inflammation
• Often referred to as the anemia of chronic
disease, anemia associated with chronic
inflammation is the most common form of
anemia in hospitalized patients.
• suppression of erythropoiesis by systemic
inflammation.
43. It occurs in a variety of disorders associated with
sustained inflammation:
• Chronic microbial infections, such as
osteomyelitis, bacterial endocarditis, and lung
abscess.
• Chronic immune disorders, such as
rheumatoid arthritis and regional enteritis
• Neoplasms, such as Hodgkin lymphoma and
carcinomas of the lung and breast
44. Pathogenesis
• The anemia of chronic inflammation stems from
high levels of plasma hepcidin, which blocks the
transfer of iron to erythroid precursors by
downregulating ferroportin in macrophages.
• The elevated hepcidin levels are caused by
proinflammatory cytokines such as IL-6, which
increase hepatic hepcidin synthesis.
• In addition, chronic inflammation blunts
erythropoietin synthesis by the kidney, lowering
red cell production by the marrow.
45. Clinical Features
• As in anemia of iron deficiency, the serum iron
levels usually are low in the anemia of chronic
disease, and the red cells may be slightly
hypochromic and microcytic.
• Administration of erythropoietin and iron can
improve the anemia, but only effective
treatment of the underlying condition is
curative.
46. Megaloblastic Anemias
• The two principal causes of megaloblastic
anemia are folate deficiency and vitamin B12
deficiency.
• Both vitamins are required for DNA synthesis
and the effects of their deficiency on
hematopoiesis are essentially identical.
47. Pathogenesis
• Megaloblastic anemia stems from metabolic
defects that lead to inadequate biosynthesis of
thymidine, one of the building blocks of DNA.
• Folate and vitamin B12 are both essential factors
for the synthesis of thymidylate, which is required
for DNA replication.
• Thymidine deficiency causes abnormalities in
rapidly dividing cells throughout the body, but
the hematopoietic marrow is most severely
affected
48. • Because the synthesis of RNA and cytoplasmic
elements proceeds at a normal rate and thus
outpaces that of the nucleus, the
hematopoietic precursors show nuclear-
cytoplasmic asynchrony.
• This maturational derangement contributes to
the anemia in several ways. Many red cell
progenitors are so defective in DNA synthesis
that they undergo apoptosis in the marrow
(ineffective hematopoiesis)
49. Folate (Folic Acid) Deficiency Anemia
• Folate deficiency is usually the result of inadequate
dietary intake, sometimes complicated by increased
metabolic demands.
• Although folate is present in nearly all foods, it is
destroyed by 10 to 15 minutes of cooking, and as a
result folate stores are marginal in a surprising number
of healthy persons.
• The risk of overt folate deficiency is highest in those
with a poor diet (the economically deprived, the
indigent, and the elderly) or those with increased
metabolic needs (pregnant women and patients with
chronic hemolytic anemias, such as sickle cell disease).
50. • Deficiency may also stem from problems with
absorption or metabolism. Food folates are
predominantly in polyglutamate form and must
be split into monoglutamates for absorption, a
conversion that is inhibited by acidic foods and
substances found in beans and other legumes.
• Some drugs, such as phenytoin (dilantin), also
interfere with folate absorption, whereas others,
such as methotrexate, inhibit folate metabolism.
• Malabsorptive disorders, such as celiac disease
and tropical sprue, that affect the upper third of
the small intestine where folate is absorbed, may
also impair folate uptake.
51. Pathogenesis
• Here it is sufficient to note that its conversion
within cells from dihydrofolate to
tetrahydrofolate by dihydrofolate reductase is
particularly important.
• Tetrahydrofolate acts as an acceptor and donor of
one-carbon units in several reactions that are
required for the synthesis of deoxythymidine
monophosphate (dTMP).
• If intracellular stores of folate fall, insufficient
dTMP is synthesized and DNA replication is
blocked, leading to megaloblastic anemia.
52. Clinical Features
• The clinical picture may be complicated by the
coexistent deficiency of other vitamins,
especially in alcoholics.
• Because the cells lining the gastrointestinal
tract, like the hematopoietic system, turn over
rapidly, symptoms referable to the alimentary
tract, such as sore tongue, are common.
• Unlike in vitamin B12 deficiency, neurologic
abnormalities do not occur.
53. Vitamin B12 (Cobalamin) Deficiency
Anemia
• Vitamin B12 is widely present in foods, is
resistant to cooking and boiling, and is even
synthesized by gut flora.
• Thus, unlike folate, vitamin B12 deficiency is
virtually never caused by inadequate intake
except in vegetarians who scrupulously avoid milk
and eggs.
• Instead, deficiencies typically arise from some
abnormality that interferes with vitamin B12
absorption, a complex process involving the
following steps
54. 1. Peptic digestion releases dietary vitamin B12,
allowing it to bind a salivary protein called
haptocorrin.
2. On entering the duodenum, haptocorrin–B12
complexes are processed by pancreatic
proteases; this releases B12, which attaches to
intrinsic factor secreted from the parietal cells of
the gastric fundic mucosa.
3. The intrinsic factor–B12 complexes pass to the
distal ileum and attach to cubilin, a receptor for
intrinsic factor, and are taken up into enterocytes.
4. The absorbed vitamin B12 is transferred across
the basolateral membranes of enterocytes to
plasma transcobalamin, which delivers vitamin
B12 to the liver and other cells of the body.
55. • It is stored in the liver, which normally
contains reserves sufficient to support bodily
needs for 5 to 20 years.
• Because of these large liver stores, clinical
presentations of vitamin B12 deficiency
typically follow years of unrecognized
malabsorption.
56. Pathogenesis
• The most frequent cause vitamin B12 deficiency
is pernicious anemia, which is believed to result
from an autoimmune attack on the gastric
mucosa that suppresses the production of
intrinsic factor.
• The serum of most affected patients contains
several types of autoantibodies that block the
binding of vitamin B12 to intrinsic factor or
prevent binding of the intrinsic factor–vitamin
B12 complex to cubilin
57. • The main neurologic lesions associated with
vitamin B12 deficiency are demyelination of
the posterior and lateral columns of the spinal
cord, sometimes beginning in the peripheral
nerves. In time, axonal degeneration may
supervene.
58. Clinical Features
• Pallor
• easy fatigability
• in severe cases, dyspnea and even congestive
heart failure
• mild jaundice
• megaloblastic changes in the oropharyngeal
epithelium may produce a beefy red tongue.
• The spinal cord disease begins with symmetric
numbness, tingling, and burning in the feet or
hands, followed by unsteadiness of gait and loss
of position sense, particularly in the toes.
59. • Findings supporting the diagnosis of vitamin
B12 deficiency are
• (1) low serum vitamin B12 levels,
• (2) normal or elevated serum folate levels,
• (3) moderate to severe macrocytic anemia,
• (4) leukopenia with hypersegmented
granulocytes, and
• (5) a dramatic reticulocytic response (within 2
to 3 days) to parenteral administration of
vitamin B12.
60. Aplastic Anemia
• Aplastic anemia is a disorder in which
multipotent myeloid stem cells are suppressed,
leading to bone marrow failure and
pancytopenia.
Pathogenesis
• The pathogenesis of aplastic anemia is not fully
understood, but two major etiologies have been
invoked:
• an extrinsic, immune-mediated suppression of
marrow progenitors,
• and an intrinsic abnormality of stem cells.
61. Myelophthisic Anemia
• Myelophthisic anemia is caused by extensive
infiltration of the marrow by tumors or other
lesions.
• It most commonly is associated with metastatic
breast, lung, or prostate cancer. Other tumors,
advanced tuberculosis, lipid storage disorders,
and osteosclerosis may produce a similar clinical
picture.
• The principal manifestations include anemia and
thrombocytopenia; in general, the white cell
series is less affected. Characteristically
misshapen red cells, some resembling teardrops,
are seen in the peripheral blood
62. POLYCYTHEMIA
• Polycythemia, or erythrocytosis, denotes an
increase in red cells per unit volume of
peripheral blood. It may be absolute (defined
as an increase in total red cell mass) or
relative.
• Relative polycythemia results from
dehydration, such as occurs with water
deprivation, prolonged vomiting, diarrhea, or
the excessive use of diuretics.
63. • Absolute polycythemia is described as primary
when the increased red cell mass results from
an autonomous proliferation of erythroid
progenitors, and secondary when the
excessive proliferation stems from elevated
levels of erythropoietin.